Tocilizumab for severe COVID-19 related illness – A community academic medical center experience

Meleveedu, Kapil; Miskovsky, John; Meharg, Joseph; Abdelrahman, Abd Almonem M.; Tandon, R. N.; Moody, Ashley; Dasilva, Priscilla; Massé, G.; LaPorte, Jason; Calvino, Abdul Saied; Allen, Greg; El-Bizri, R.; Roberts, Todd F.; Armenio, Vincent; Katz, Steven C.

doi:10.1016/j.cytox.2020.100035

Cited by 7 publications

(7 citation statements)

References 30 publications

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“…However, all antibodies prevent the binding of IL-6 to IL-6R and inhibit classic and trans -signaling equally well ( 30 ). Consistently, the IL-6R antibodies tocilizumab and sarilumab demonstrated beneficial effects on survival rates in severe COVID-19 cases in preclinical and clinical studies ( 9 – 11 , 31 ). However, IL-6 is required to control viral infection ( 32 ); hence, global blockade of IL-6 signaling, e.g., through tocilizumab, is associated with an increased risk of airway infections ( 33 , 34 ).…”

Section: Introductionmentioning

confidence: 71%

A Hybrid Soluble gp130/Spike-Nanobody Fusion Protein Simultaneously Blocks Interleukin-6 trans -Signaling and Cellular Infection with SARS-CoV-2

Ettich

Werner

Weitz

et al. 2022

J Virol

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SARS-CoV2 infection can induce mild to life threatening symptoms. Especially individuals over 60 years of age or with underlying co-morbidities including heart or lung disease, and diabetes or immune compromised patients are at higher risk. Fatal multi-organ damage in COVID19 patients can be attributed to Interleukin (IL-)6 dominated cytokine storm. Consequently, IL-6R monoclonal antibody treatment for severe COVID19 cases has been approved for therapy. High concentrations of soluble IL-6R were found in COVID19 intensive care unit patients suggesting the involvement of IL-6 trans-signaling in disease pathology. Here, in analogy to bispecific antibodies (bsAbs), we developed the first bispecific IL-6 trans-signaling inhibitor c19s130Fc which blocks viral infection and IL-6 trans-signaling. c19s130Fc is a designer protein of the IL-6 trans-signaling inhibitor cs130 fused to a single domain nanobody directed against the receptor binding domain (RBD) of the SARS-CoV2 spike protein. c19s130Fc binds with high affinity to IL-6:sIL6R complexes as well as the spike protein of SARS-CoV2 as shown by surface plasmon resonance. Using cell-based assays, we demonstrate that c19s130Fc blocks IL-6 trans-signaling-induced proliferation and STAT3 phosphorylation of Ba/F3-gp130 cells as well as SARS-CoV2 infection and STAT3 phosphorylation in Vero cells. Taken together, c19s130Fc represents a new class of bispecific inhibitors consisting of a soluble cytokine receptor fused to anti-viral nanobodies and principally demonstrates the multi-functionalization of trans-signaling inhibitors. Importance The availability of effective SARS-CoV2 vaccines is a big step forward in managing the pandemic situation. In addition, therapeutic options e.g. monoclonal antibodies to prevent viral cell entry and anti-inflammatory therapies including glucocorticoid treatment are currently developed or in clinical use utilized to treat already infected patients. Here we report a novel dual-specific inhibitor to simultaneously target SARS-Cov2 infection and virus induced hyper-inflammation. This was achieved by fusing an inhibitor of viral cell entry with a molecule blocking IL-6, a key mediator of SARS-CoV2 induced hyper-inflammation. Through this dual action, this molecule may have the potential to efficiently ameliorate symptoms of COVID19 in infected individuals.

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Section: Introductionmentioning

confidence: 71%

A Hybrid Soluble gp130/Spike-Nanobody Fusion Protein Simultaneously Blocks Interleukin-6 trans -Signaling and Cellular Infection with SARS-CoV-2

Ettich

Werner

Weitz

et al. 2022

J Virol

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“…Tocilizumab (TCZ) is a well-established IL-6 receptor monoclonal antibody that inhibits both the classical and trans-signaling axis widely used for the PLOS PATHOGENS treatment of rheumatoid arthritis. Several clinical outcomes suggested that an early use of tocilizumab is beneficial for survival, reduction of hospitalization stay, and duration of oxygen support in COVID-19 patients [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells

et al. 2020

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Cytokine storm is suggested as one of the major pathological characteristics of SARS-CoV-2 infection, although the mechanism for initiation of a hyper-inflammatory response, and multi-organ damage from viral infection is poorly understood. In this virus-cell interaction study, we observed that SARS-CoV-2 infection or viral spike protein expression alone inhibited angiotensin converting enzyme-2 (ACE2) receptor protein expression. The spike protein promoted an angiotensin II type 1 receptor (AT1) mediated signaling cascade, induced the transcriptional regulatory molecules NF-κB and AP-1/c-Fos via MAPK activation, and increased IL-6 release. SARS-CoV-2 infected patient sera contained elevated levels of IL-6 and soluble IL-6R. Up-regulated AT1 receptor signaling also influenced the release of extracellular soluble IL-6R by the induction of the ADAM-17 protease. Use of the AT1 receptor antagonist, Candesartan cilexetil, resulted in down-regulation of IL-6/soluble IL-6R release in spike expressing cells. Phosphorylation of STAT3 at the Tyr705 residue plays an important role as a transcriptional inducer for SOCS3 and MCP-1 expression. Further study indicated that inhibition of STAT3 Tyr705 phosphorylation in SARS-CoV-2 infected and viral spike protein expressing epithelial cells did not induce SOCS3 and MCP-1 expression. Introduction of culture supernatant from SARS-CoV-2 spike expressing cells on a model human liver endothelial Cell line (TMNK-1), where transmembrane IL-6R is poorly expressed, resulted in the induction of STAT3 Tyr705 phosphorylation as well as MCP-1 expression. In conclusion, our results indicated that the presence of SARS-CoV-2 spike protein in epithelial cells promotes IL-6 trans-signaling by activation of the AT1 axis to initiate coordination of a hyper-inflammatory response.

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“…Intravenous antibiotics were given to patients with elevated procalcitonin, positive sputum or blood culture and/or elevated CRP in whom concurrent bacterial infection was suspected. Tocilizumab was administered to patients who had the following parameters: ferritin ≥600 ng/mL, CRP ≥80 mg/L 32 and IL-6 >37.65 pg/ml. 33 We recorded 10 (16.4%) deaths during the study period, all of which occurred among the RC group.…”

Section: Resultsmentioning

confidence: 99%

Combination of cycle threshold time, absolute lymphocyte count and neutrophil:lymphocyte ratio is predictive of hypoxia in patients with SARS-CoV-2 infection

Abeysuriya

Seneviratne

Silva

et al. 2021

Transactions of the Royal Society of Tropical Medicine and Hygiene

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Background There is currently no clinically validated biomarker to predict respiratory compromise in sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cycle threshold time (Ct), absolute lymphocyte count (AL) and neutrophil:lymphocyte ratio (NLR) have been previously evaluated for this purpose. We hypothesized that the combination of these parameters at presentation may be predictive of hypoxia (oxygen saturation <92%). Methods Data were collected on 118 patients with SARS-CoV-2 infection between May 2020 and April 2021. Demographics, clinical parameters and laboratory and radiological investigation results were recorded. Respiratory compromise (RC) was defined based on symptoms and signs, hypoxia and chest X-ray abnormalities. Results RC occurred in 61 (51.7%) of patients. The Ct, AL and NLR at median day 3 of illness were significantly different between patients with and without RC (Ct, RC vs not: 19.46±2.64 vs 22.62±3.37, p=0.0001; AL, RC vs not: 531.49±289.09 vs 764.69±481.79, p=0.0001; NLR, RC vs not: 3.42±0.75 vs 2.59±0.55, p=0.0001). Receiver operating characteristics analysis showed that a Ct <19.9, AL <630.8×103/μL and NLR >3.12 at median day 3 of symptoms was predictive of hypoxia on day 7 of illness (area under the curve 0.805, sensitivity 96.7%, specificity 69.1%). The predictive value for the parameters combined was significantly superior to their individual predictive power. Conclusions Ct, AL and NLR used in combination on day 3 of symptoms are predictive of hypoxia on day 7 of SARS-CoV-2 illness.

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Tocilizumab for severe COVID-19 related illness – A community academic medical center experience

Cited by 7 publications

References 30 publications

A Hybrid Soluble gp130/Spike-Nanobody Fusion Protein Simultaneously Blocks Interleukin-6 trans -Signaling and Cellular Infection with SARS-CoV-2

A Hybrid Soluble gp130/Spike-Nanobody Fusion Protein Simultaneously Blocks Interleukin-6 trans -Signaling and Cellular Infection with SARS-CoV-2

SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells

Combination of cycle threshold time, absolute lymphocyte count and neutrophil:lymphocyte ratio is predictive of hypoxia in patients with SARS-CoV-2 infection

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